GLP-1 is an important gut hormone with regulatory function in glucose metabolism and gastrointestinal secretion and metabolism. Human GLP-1 is a 30 amino acid peptide originating from preproglucagon, which is synthesized for example, in the L-cells in the distal ileum, in the pancreas and in the brain. Processing of preproglucagon to yield GLP-1 (7-36) amide and GLP-2 occurs mainly in the L-cells and the brainstem. GLP-1 is normally secreted in response to the intake of food, particularly carbohydrates and lipids, and it has been identified as a very potent and efficacious stimulator of glucose-dependent insulin release with a reduced risk to induce hypoglycemia. GLP-1 also lowers plasma glucagon concentrations, slows gastric emptying, stimulates insulin biosynthesis and enhances insulin sensitivity (Nauck, Horm. Metab. Res., 29(9):411-416 (1997)) It also enhances the ability of the pancreatic beta-cells to sense and respond to glucose in subjects with impaired glucose tolerance (Byrne, M. M. et al., Eur. J. Clin. Invest., 28(1):72-78 (1998)). The insulinotropic effect of GLP-1 in humans increases the rate of glucose metabolism partly due to increased insulin levels and partly due to enhanced insulin sensitivity (D'Alessio, J Clin Invest. 93(5):2263-66 (1994)). Inhibition of glucagon release is thought to be an additional mechanism which contributes to the improvements in glucose homeostasis observed following treatment of type II diabetic patients with GLP-1 (Nauck, M. A. et al., Diabetologia, 36(8):741-744 (1993)). These pharmacological properties make GLP-1 a highly desirable therapeutic agent for the treatment of type-II diabetes.
Research has been conducted to develop drug delivery techniques and compositions to allow agent delivery at a rates that allow maintenance of drug concentrations at therapeutically effective levels for extended periods of time. For example, one method of making delayed or sustained release formulations involves coating the tablet with a release-delaying coating, or coating individual granules with such a coating, and compressing these coated granules into tablets. However, during preparation of delayed, or sustained release drug formulations, use of relatively high concentrations of soluble polymers may result in slow drug dissolution, poor or variable drug release, poor or variable absorption, and acid instability over the range of the pH environment in the gastrointestinal (GI) tract.
Research has been conducted to develop drug delivery techniques and compositions to allow agent delivery at rates that allow maintenance of drug concentrations at therapeutically effective levels for extended periods of time. For example, biodegradable polymeric drug delivery formulations have been developed and utilized for the controlled in vivo release of drugs. See, e.g., U.S. Pat. Nos. 3,773,919 and 4,767,628. Such biodegradable polymeric formulations are designed to slowly release an entrapped drug by diffusion through a polymer matrix and/or as the biodegradable polymer is depolymerized. International Publication No. WO 94/15587 concerns sustained release ionic molecular conjugates of polyesters and drugs. Since both diffusion and polyester degradation may control the release process, the surface area of the polymeric particles can influence the release profile of the entrapped drug. Thus, such particles should be of similar size and shape to insure reproducible surface area.
Therapy involving the use of GLP-1-type molecules presents a significant problem because the serum half-life of GLP-1 peptides is short. For example, GLP-1 (7-37) has a serum half-life of less than 5 minutes. Thus, there exists a need to extend the half-life of GLP-1 peptides to enhance their therapeutic effect. The subject matter disclosed and claimed herein fulfills this need by providing novel pharmaceutical compositions comprising a metal ion (e.g., zinc) and a GLP-1 receptor modulator adduct in a sustained release formulation. As such, these compositions are useful for the amelioration of diabetes and related conditions. The compositions are appealing to patients and physicians because a sustained release composition requires less frequent administration as compared to other formulations.